DESCRIPTION: (Applicant's Abstract) We have discovered a simple analog of methyllycaconitine (MLA) that acts as a micromolar inhibitor at the nicotinic acetylcholine receptor nAChR). This should be a fertile area from which to find selective and potent antagonists of subtypes of the nAChR. The goal of this proposal is to quickly outline an SAR (Structure Activity Relationship) of this new lead compound in order to assess structural requirements necessary for potency and selectivity. This will lead to new pharmacological tools as well as aid in the development of novel nAChR antagonists as drugs. Through a systematic evaluation of substituents on the nitrogen of the piperidine ring as well as alterations to the piperidine ring itself, we will determine an optimal group with regard to potency and receptor subtype specificity. We will also prepare differently substituted imides in order to determine the optimal placement with regard to potency and receptor subtype specificity. All analogs will be evaluated with regard to the potency and receptor subtype specificity. MLA is extremely interesting as a lead compound for the development of new nAChR antagonists. MLA is the most potent non-peptide nAChR antagonist currently known. Since the availability of MLA from natural sources is limited, very little work on understanding the SAR of MLA has been reported. While several analogs of MLA have been synthesized only a few reports of biological activity have been published. These previous analogs have failed to fully define the pharmacophore of MLA. We describe a series of analogs that will allow us to develop a detailed pharmacophore of the nicotinic antagonist MLA. Our analogs are novel, rapidly prepared, and target the two most significant portions of MLA for study. These key structural features will allow us to expeditiously arrive at a detailed pharmacophore for MLA. These studies have the potential to be the first step for extensive future work on the design and discovery of novel nicotinic agents. These types of compounds have potential use as pharmacological tools and aids in understanding and treating nicotine addiction.